title: The ankyrin-3 gene is associated with posttraumatic stress disorder and externalizing comorbidity.
abstract: BACKGROUND
  The ankyrin 3 gene (ANK3) produces the ankyrin G protein that plays an integral role in regulating neuronal activity. Previous studies have linked ANK3 to bipolar disorder and schizophrenia. A recent mouse study suggests that ANK3 may regulate behavioral disinhibition and stress reactivity. This led us to hypothesize that ANK3 might also be associated with stress-related psychopathology such as posttraumatic stress disorder (PTSD), as well as disorders of the externalizing spectrum such as antisocial personality disorder and substance-related disorders that are etiologically linked to impulsivity and temperamental disinhibition.
  
  
  METHODS
  We examined the possibility of association between ANK3 SNPs and both PTSD and externalizing (defined by a factor score representing a composite of adult antisociality and substance abuse) in a cohort of white non-Hispanic combat veterans and their intimate partners (n=554). Initially, we focused on rs9804190-a SNP previously reported to be associated with bipolar disorder, schizophrenia, and ankyrin G expression in brain. Then we examined 358 additional ANK3 SNPs utilizing a multiple-testing correction.
  
  
  RESULTS
  rs9804190 was associated with both externalizing and PTSD (p=0.028 and p=0.042 respectively). Analysis of other ANK3 SNPs identified several that were more strongly associated with either trait. The most significant association with externalizing was observed at rs1049862 (p=0.00040, pcorrected=0.60). The most significant association with PTSD (p=0.00060, pcorrected=0.045) was found with three SNPs in complete linkage disequilibrium (LD)-rs28932171, rs11599164, and rs17208576.
  
  
  CONCLUSIONS
  These findings support a role of ANK3 in risk of stress-related and externalizing disorders, beyond its previous associations with bipolar disorder and schizophrenia.
authors.affiliation: Biomedical Genetics, Department of Medicine, Boston University School of Medicine, Boston, MA, United States; Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Logue
authors.forename: Nadia
authors.initials: N
authors.lastname: Solovieff
authors.forename: Melanie P
authors.initials: MP
authors.lastname: Leussis
authors.forename: Erika J
authors.initials: EJ
authors.lastname: Wolf
authors.forename: Efthymia
authors.initials: E
authors.lastname: Melista
authors.forename: Clinton
authors.initials: C
authors.lastname: Baldwin
authors.forename: Karestan C
authors.initials: KC
authors.lastname: Koenen
authors.forename: Tracey L
authors.initials: TL
authors.lastname: Petryshen
authors.forename: Mark W
authors.initials: MW
authors.lastname: Miller
mesh_terms: D000328:Adult; D000368:Aged; D017487:Ankyrins / Q000235:genetics*; D015897:Comorbidity; D019260:Expressed Emotion / Q000502:physiology; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000453:epidemiology / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D013313:Stress Disorders, Post-Traumatic / Q000453:epidemiology / Q000235:genetics*; D014728:Veterans / Q000523:psychology / Q000706:statistics & numerical data; D055815:Young Adult
chemical_list: C490613:ANK3 protein, human; D017487:Ankyrins
keywords: ANK3; Candidate gene; Externalizing; Genetic association; Posttraumatic stress disorder